SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2019, 51, 146–160 short review 146 en Syn thesis W. Erb, F. Mongin Short Review Twofold Ferrocene C–H Lithiations For One-Step Difunctionaliza- tions William Erb* 0000-0002-2906-2091 R(*) Florence Mongin* 0000-0003-3693-8861 E E R E Fe Fe E Fe Fe Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) - E E E UMR 6226, 35000 Rennes, France (*)R [email protected] E [email protected] (*)R E R E Fe Fe Fe Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue E E E R(*) R(*) R Received: 29.10.2018 Accepted: 05.11.2018 Published online: 05.12.2018 DOI: 10.1055/s-0037-1610396; Art ID: ss-2018-z0724-sr License terms: Abstract For some aromatics, a twofold C–H deprotolithiation can be achieved, allowing these compounds to be subsequently difunctional- ized in one step. This short review brings together examples in which ferrocenes are converted in this way. 1 Introduction 2 Bare Ferrocene 3 Ferrocenes Substituted by Alkyl or Silyl Groups William Erb obtained his Ph.D. in organic chemistry in 2010 under the 4 Ferrocenes Substituted by Aminoalkyls supervision of Prof. Jieping Zhu on the total synthesis of natural prod- 5 Ferrocenes Substituted by Halogens or Oxygen-Based Groups ucts and palladium-catalyzed reactions. During the next four years of 6 Ferrocenes Substituted by Alkoxyalkyls or Acetals postdoctoral studies he worked in various laboratories on different re- 7 Ferrocenes Substituted by Sulfoxides search projects from organocatalysis to supramolecular chemistry with 8 Ferrocenes Substituted by Oxazolines an emphasis on the development of new methodologies (University of 9 Ferrocenes Substituted by Carboxamides Bristol, Prof. Varinder Aggarwal, UK - ESPCI, Prof. Janine Cossy, Paris - 10 Conclusion LCMT, Prof. Jacques Rouden, Caen - COBRA, Prof. Géraldine Gouhier, Rouen). He was appointed assistant professor at the University of Key words ferrocene, deprotolithiation, dilithio compounds, electro- Rennes (France) in 2015 where he is mainly working on the develop- philic trapping, planar chirality, chiral directing group, chiral ligand, fer- ment of original ferrocene functionalizations. rocenophane Florence Mongin obtained her Ph.D. in chemistry in 1994 from the University of Rouen (France) under the supervision of Prof. Guy Que- 1 Introduction guiner. After a two-year stay at the Institute of Organic Chemistry of Lausanne (Switzerland) as a postdoctoral fellow with Prof. Manfred Schlosser, she returned to the University of Rouen as an Assistant Pro- Aromatic organolithiums can be prepared by different fessor in 1997 (HDR in 2003). She took up her present position in 2005 as Professor at the University of Rennes (France) and was appointed Ju- methodologies including halogen/metal exchange, C–H nior Member of the Institut Universitaire de France in 2009. Her present lithiation, transmetalation, and C–heteroatom bond cleav- scientific interests include the functionalization of aromatic compounds age.1 Twofold C–H deprotonation followed by electrophilic including heterocycles with recourse to bimetallic bases or combina- trapping has attracted numerous synthetic organic chem- tions. ists because the approach allows two functionalizations to be achieved at once in a one-pot process. Substrates bene- fiting from relatively acidic hydrogens, either because the cenes, benzenes, and benzo-fused derivatives, for which the corresponding carbanions are stabilized by electron delo- pKa values are ~30–35 or above, presents an important syn- calization or inductively owing to the presence of electron- thetic challenge. Indeed, because of the highly ionic charac- withdrawing groups, can be readily dideprotonated. In con- ter of their C–Li bonds, the corresponding dilithio com- trast, twofold sp2-C–H lithiation of substrates such as ferro- pounds are very reactive. Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 146–160 147 Syn thesis W. Erb, F. Mongin Short Review Since the discovery and structural elucidation of ferro- Table 1 Dideprotolithiation of Ferrocene in Hexane Followed by Differ- cene in 1951,2 the first sandwich compound rapidly be- ent Electrophilic Trappings came a key player in chemistry due to unequalled redox 1) BuLi–TMEDA H E properties, three-dimensional structure, and air and ther- (n equiv) 3 mal stability. It has since been incorporated into various li- Fe hexane, r.t., t (h) Fe gands (in particular chiral ones) for homogeneous cataly- H 2) Electrophile E sis,4 in materials endowed with various (e.g., optical, elec- tronic, and magnetic) properties,3,5 and in biologically n equiv, t (h) Electrophile (E) Yielda (%) active compounds.6 2.5, 6 CO then H+ (CO H) 9415 Among the methods used to functionalize ferrocenes, 2 2 2.5, 6 Ph C=O [C(OH)Ph ]8015 deprotometalation is probably the most convenient strate- 2 2 gy, allowing various derivatives to be prepared regioselec- 2.5, 6 pyridine (2-pyridyl) 3015 tively.4b,d,h,7 In this short review, our goal is to update the 2.2, overnight DMF (CHO) 8516a b 16b approaches to dideprotolithiate and subsequently difunc- 2.1, 22 H2C=NMe2I (CH2NMe2)57 tionalize ferrocene and its derivatives. 16c 2.2, overnight ClCO2i-Pr (CO2i-Pr) 58 (18) 2.2, overnight ClCOPh (COPh) 65 (16)16c 2 Bare Ferrocene 2.2, overnight ClTs (Cl) 64 (15)16c 16d 16e 2.2-2.5, 6 to overnight (CCl3)2 (Cl) 60, 75 8 16d The dideprotolithiation of ferrocene being more likely 2.5, 6 Br2 (Br) 23 9 16c than that of benzene, it quickly established itself as a reac- 2.2, overnight (CBrCl2)2 (Br) 89 10 tion competitive to monolithiation. Dismutation of lithio- 16f 2.1, overnight (CHBr2)2 (Br) 67 ferrocene to afford 1,1′-dilithioferrocene and ferrocene is at 2.2 to 2.5, 6 to 16 I (I) 55,16d 60,16c 7216g the origin of this issue.11 In spite of thorough studies in or- 2 c 16e 16h der to get clean ferrocene monolithiation,12 competitive for- 2.2, overnight NFSI (F) 2, 9 16i mation of 1,1′-dilithioferrocene could only be avoided in 2.5, 6 (ClBNMe2)2 [(BNMe2)2]58 13 16j the presence of catalytic potassium tert-butoxide. What 2.5, 6 ClSiMe3 (SiMe3) n.r. was initially a problem, competitive dideprotolithiation, 16k 2.5, 6 ClSi(OMe)3 [Si(OMe)3]52 turned out to be an opportunity, with numerous studies 16l 16m 2.3 to 2.5, 6 to 16 ClSi(OEt)3 [Si(OEt)3] 64, 50 dedicated to the synthesis of 1,1′-difunctionalized ferro- 2.0, 18 ClPt-Bu (Pt-Bu ) n.r.16n cenes using this possibility. 2 2 16o Tetrahydrofuran (THF) is not a solvent in which alkyl- 2.0, 18 ClP(Ph)t-Bu [P(Ph)t-Bu] 60 16c lithium-mediated dimetalation of ferrocene can be carried 2.2, overnight ClPPh2 (PPh2)73 16p out efficiently. Indeed, subsequent electrophilic trapping 2.2, 12 ClP(NEt2)2 [P(NEt2)2]80 shows that, in addition to remaining starting material, mix- 16c 2.2, overnight ClPO(OEt)2 [PO(OEt)2] 60 (22) tures of monolithio- and 1,1′-dilithioferrocenes are, in gen- 2.4, 24 ClPO(Oi-Pr) [PO(Oi-Pr) ]8216q eral, formed.13 2 2 2.1, 3 (SMe) (SMe) 7016r In 1964, Eberhardt and Butte discovered the impact of 2 16r ligands, TMEDA (TMEDA = N,N,N′,N′-tetramethylethylenedi- 2.1, 3 (Si-Pr)2 (Si-Pr) 73 16c amine) and sparteine, in enhancing the reactivity of the al- 2.0, overnight (SPh)2 (SPh) 70 14 16s kyllithium reagents through the formation of chelates. 2.0, 18 IAsMe2 (AsMe2)54 Unlike butyllithium, the butyllithium–TMEDA chelate (2.0 16s 2.0, 18 ClAsPh2 (AsPh2)57 to 2.5 equiv; formed from the components after stirring for a Yield in parenthesis is of the competitively formed 1-substituted ferro- a few minutes at 25 °C) can easily 1,1′-dimetalate ferrocene cene; n.r. = yield not reported. in hexane at 25 °C, a result first evidenced by Rausch and b Eschenmoser’s salt. c N-Fluorobenzenesulfonimide. Ciappenelli in 1967.15 Subsequent quenching using various electrophiles allowed many 1,1′-disubstituted ferrocenes to be obtained (Table 1).15,16 has been illustrated here (not exhaustively) to highlight the As exemplified in Table 2, ferrocenophanes can be simi- variety of electrophiles that can be employed to intercept larly obtained from 1,1′-dilithioferrocene, but by trapping 1,1′-dilithioferrocene. with bis-electrophiles such as dichlorides.16m,p,17 Ferroceno- Using diethyl ether as hexane cosolvent still proved con- phanes (or ansa-bridged systems) are a widely developed venient to access 1,1′-disubstituted ferrocenes (Table 3).20 field18 on which there is much to be said, even including ex- Solid-state structures were recorded for chelates of 1,1′- amples with nickel, palladium, and platinum bridges.19 It dilithioferrocene with PMDTA (PMDTA = N,N,N′,N′′,N′′-pen- Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 146–160 148 Syn thesis W. Erb, F. Mongin Short Review Table 2 Dideprotolithiation of Ferrocene in Hexane Followed by Con- Table 3 Dideprotolithiation of Ferrocene in Diethyl Ether/Hexane Fol- versions into Ferrocenophanes lowed by Different Electrophilic Trappings 1) BuLi–TMEDA H 1) BuLi–TMEDA (n equiv) (n equiv) H E Fe hexane, r.t., t (h) Fe E or Fe E Fe Et2O–hexane r.t., t (h) Fe Fe or Fe E H 2) Electrophile H 2) Electrophile E n equiv, t (h)Electrophile (E) Yielda (%) n equiv, t (h) Electrophile (E) Yielda (%) 2.3, 16 Cl SiCl (SiCl ) 50,16m 80–9017a 2 2 2 2.5, 24 DMF (CHO) 8520a,b 2.5, 18 Cl SiPh (SiPh )3217b,c 2 2 2 2.5, 24 PhCHO [CH(OH)Ph] 9120a 17d 2.3, 16 Cl2SiMe2 (SiMe2)60 20a 2.5, 24 (CH2O)n [CH2OH] 43 17b 16p 17e 2.3, 16 Cl2SiCl2 (Si) 17, 56, 70 20c 2.7, 24 Ph2CO [C(OH)Ph] 93 16p 17e 2.3, 16 Cl2Si(CH2)3 [Si(CH2)3] 71, 79 20a